Toward the Development of a General Chiral Auxiliary. A Total Synthesis of (+)-Tetronolide via a Tandem Ketene-Trapping [4 + 2] Cycloaddition Strategy

Boeckman, Robert K.; Shao, Pengcheng; Wrobleski, Stephen T.; Boehmler, Debra J.; Heintzelman, Geoffrey R.; Barbosa, Antonio. J.

doi:10.1021/ja0581346

Cited by 61 publications

(37 citation statements)

References 61 publications

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“…Since the mid 1980s, extensive attempts to synthesize aglycones have been made, resulting in the total synthesis of (ϩ)-tetronolide of TCA and (Ϫ)-chlorothricolide of chlorothricin (CHL) (the first member to be discovered and structurally elucidated in this family [Fig. 1]) (4,30,31,36). However, the synthesis of the entire molecule of either TCA or CHL has not yet been achieved.…”

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confidence: 99%

Cloning and Characterization of the Tetrocarcin A Gene Cluster from Micromonospora chalcea NRRL 11289 Reveals a Highly Conserved Strategy for Tetronate Biosynthesis in Spirotetronate Antibiotics

et al. 2008

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Tetrocarcin A (TCA), produced by Micromonospora chalcea NRRL 11289, is a spirotetronate antibiotic with potent antitumor activity and versatile modes of action. In this study, the biosynthetic gene cluster of TCA was cloned and localized to a 108-kb contiguous DNA region. In silico sequence analysis revealed 36 putative genes that constitute this cluster (including 11 for unusual sugar biosynthesis, 13 for aglycone formation, and 4 for glycosylations) and allowed us to propose the biosynthetic pathway of TCA. The formation of D-tetronitrose, L-amicetose, and L-digitoxose may begin with D-glucose-1-phosphate, share early enzymatic steps, and branch into different pathways by competitive actions of specific enzymes. Tetronolide biosynthesis involves the incorporation of a 3-C unit with a polyketide intermediate to form the characteristic spirotetronate moiety and trans-decalin system. Further substitution of tetronolide with five deoxysugars (one being a deoxynitrosugar) was likely due to the activities of four glycosyltransferases. In vitro characterization of the first enzymatic step by utilization of 1,3-biphosphoglycerate as the substrate and in vivo cross-complementation of the bifunctional fused gene tcaD3 (with the functions of chlD3 and chlD4) to ⌬chlD3 and ⌬chlD4 in chlorothricin biosynthesis supported the highly conserved tetronate biosynthetic strategy in the spirotetronate family. Deletion of a large DNA fragment encoding polyketide synthases resulted in a non-TCA-producing strain, providing a clear background for the identification of novel analogs. These findings provide insights into spirotetronate biosynthesis and demonstrate that combinatorial-biosynthesis methods can be applied to the TCA biosynthetic machinery to generate structural diversity.

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confidence: 99%

Cloning and Characterization of the Tetrocarcin A Gene Cluster from Micromonospora chalcea NRRL 11289 Reveals a Highly Conserved Strategy for Tetronate Biosynthesis in Spirotetronate Antibiotics

et al. 2008

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“…Inspired by Boeckman’s elegant tetronolide synthesis, 16 we hoped to make use of an intramolecular acylketene capture/IMDA cascade, which, to the best of our knowledge, was unprecedented in the chemical literature. Thus, thermolysis of vinyldioxinone 8 would induce a cycloreversion, expelling acetone to give transient acylketene 7 .…”

Section: Resultsmentioning

confidence: 99%

Toward a Synthesis of Hirsutellone B by the Concept of Double Cyclization

et al. 2013

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This account describes a strategy for directly forming three of the six rings found in the polyketide natural product hirsutellone B via a novel cyclization cascade. The key step in our approach comprises two transformations: a large-ring forming, nucleophilic capture of a transient acyl ketene and an intramolecular Diels–Alder reaction, both of which occur in tandem through thermolyses of appropriately functionalized, polyunsaturated dioxinones. These thermally induced “double cyclization” cascades generate three new bonds, four contiguous stereocenters, and a significant fraction of the polycyclic architecture of hirsutellone B. The advanced macrolactam and macrolactone intermediates that were synthesized by this process possess key features of the hirsutellone framework, including the stereochemically dense decahydrofluorene core and the strained para-cyclophane ring. However, attempts to complete the carbon skeleton of hirsutellone B via transannular carbon-carbon bond formation were undermined by competitive O-alkylation reactions. This account also documents how we adapted to this undesired outcome through an evaluation of several distinct strategies for synthesis, as well as our eventual achievement of a formal total synthesis of hirsutellone B.

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“…Alcohol 24 was deemed accessible from our pre‐set precursor, that is, from the bicyclo[4.4.0]decenecarboxylic ester trans ‐ 14a . The chlorosilane 22 should originate from the known enyne 23 …”

Section: Retrosynthetic Analysismentioning

confidence: 99%

“…), DIBAH (2.0 equiv. ), toluene, 0 °C, 30 min; 23 , 20 °C, 50 min; –78 °C, I 2 (2.3 equiv. ), 10 min; flash chromatography in the absence of light; (ii) n BuLi (1.05 equiv.…”

Section: Intramolecular Diels–alder Reactionsmentioning

confidence: 99%

Towards a Total Synthesis of Phenalinolactone Core Diterpenoid 6: Synthesis of a Racemic Decahydrobenzocyclobutaisobenzofuran with a trans‐anti‐cis Junction of the Isocyclic Rings

Hampel

Brückner

2017

Eur J Org Chem

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Synthetic efforts towards the “phenalinolactone core diterpenoid 6” (5) are described. It contains a cyclohexyl alcohol (A ring), a cyclohexane (B ring), and a cyclohexene (C ring), which are angularly annulated trans and cis, respectively. What makes them unique is the trans‐ (or “anti”‐) relationship between the A and the C ring. The trans‐configured A/B ring junction was established in a novel cyclohexanone annulation. Anti‐selective cis‐annulations of the C ring failed when attempted with intramolecular Diels–Alder reactions with dienes of varied electron demand (21, 31). In contrast, an anti‐selective cis‐annulation of a C ring precursor based on an intramolecular [2+2]‐photocycloaddition succeeded. It provided the tetracycle 38 in 70 % yield. It contains a densely functionalized four‐membered ring. It should lend itself to ring‐opening(s) and/or rearrangement(s). Accordingly, compound 38 should be adoptable to proceeding to the target structure 5 in future work.

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Toward the Development of a General Chiral Auxiliary. A Total Synthesis of (+)-Tetronolide via a Tandem Ketene-Trapping [4 + 2] Cycloaddition Strategy

Cited by 61 publications

References 61 publications

Cloning and Characterization of the Tetrocarcin A Gene Cluster from Micromonospora chalcea NRRL 11289 Reveals a Highly Conserved Strategy for Tetronate Biosynthesis in Spirotetronate Antibiotics

Cloning and Characterization of the Tetrocarcin A Gene Cluster from Micromonospora chalcea NRRL 11289 Reveals a Highly Conserved Strategy for Tetronate Biosynthesis in Spirotetronate Antibiotics

Toward a Synthesis of Hirsutellone B by the Concept of Double Cyclization

Towards a Total Synthesis of Phenalinolactone Core Diterpenoid 6: Synthesis of a Racemic Decahydrobenzocyclobutaisobenzofuran with a trans‐anti‐cis Junction of the Isocyclic Rings

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